Serum aldosterone and death, end-stage renal disease, and cardiovascular events in blacks and...

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Chronic kidney disease (CKD) is a major problem that affects 13% of the US population.1 Large-scale epidemio-

logical studies have demonstrated that patients with CKD have an increased risk of cardiovascular events including death, con-gestive heart failure (CHF), myocardial infarction, and stroke.2 Multiple biological pathways have been implicated in this established association between kidney disease and cardiovas-cular outcomes including activation of the renin–angiotensin–aldosterone system (RAAS). Impaired kidney function results

in RAAS activation, which in turn leads to multiple deleteri-ous cardiovascular effects, including increased volume and salt resorption, vasoconstriction, and fibrosis.3,4 An understanding of these mechanisms has resulted in the advent of multiple ther-apies including angiotensin-converting enzyme (ACE) inhibi-tors, angiotensin receptor blockers (ARBs), and aldosterone antagonists or mineralocorticoid receptor blockers (MRBs), which reduce cardiorenal complications.5 In particular, treat-ment with ACE inhibitors and ARBs slows the progression of

Abstract—Prior studies have demonstrated that elevated aldosterone concentrations are an independent risk factor for death in patients with cardiovascular disease. Limited studies, however, have evaluated systematically the association between serum aldosterone and adverse events in the setting of chronic kidney disease. We investigated the association between serum aldosterone and death and end-stage renal disease in 3866 participants from the Chronic Renal Insufficiency Cohort. We also evaluated the association between aldosterone and incident congestive heart failure and atherosclerotic events in participants without baseline cardiovascular disease. Cox proportional hazards models were used to evaluate independent associations between elevated aldosterone concentrations and each outcome. Interactions were hypothesized and explored between aldosterone and sex, race, and the use of loop diuretics and renin–angiotensin–aldosterone system inhibitors. During a median follow-up period of 5.4 years, 587 participants died, 743 developed end-stage renal disease, 187 developed congestive heart failure, and 177 experienced an atherosclerotic event. Aldosterone concentrations (per SD of the log-transformed aldosterone) were not an independent risk factor for death (adjusted hazard ratio, 1.00; 95% confidence interval, 0.93–1.12), end-stage renal disease (adjusted hazard ratio, 1.07; 95% confidence interval, 0.99–1.17), or atherosclerotic events (adjusted hazard ratio, 1.04; 95% confidence interval, 0.85–1.18). Aldosterone was associated with congestive heart failure (adjusted hazard ratio, 1.21; 95% confidence interval, 1.02–1.35). Among participants with chronic kidney disease, higher aldosterone concentrations were independently associated with the development of congestive heart failure but not for death, end-stage renal disease, or atherosclerotic events. Further studies should evaluate whether mineralocorticoid receptor antagonists may reduce adverse events in individuals with chronic kidney disease because elevated cortisol levels may activate the mineralocorticoid receptor. (Hypertension. 2014;64:103-110.) • Online Data Supplement

Key Words: aldosterone ■ death ■ heart failure ■ renal insufficiency, chronic

Received February 4, 2014; first decision February 18, 2014; revision accepted March 18, 2014.From the Department of Medicine, Division of Cardiovascular Medicine (R.D., A.M.K.) and Department of Medicine, The Renal Electrolyte and

Hypertension Division (R.R.T.), Perelman School of Medicine, University of Pennsylvania, Philadelphia; Center for Clinical Epidemiology and Biostatistics and the Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania School of Medicine, Philadelphia (W.Y., X.Z., M.B.L., H.I.F.); Department of Medicine, Division of Nephrology, University of Washington, Seattle (N.B.); Division of Nephrology, The Children’s Hospital of Philadelphia, PA (M.B.L.); Division of Cardiovascular Medicine, Temple University, Philadelphia, PA (M.G.K.); Epidemiological Cardiology Research Center (E.Z.S.), Department of Epidemiology and Prevention (E.Z.S.), and Department of Internal Medicine, Cardiology Section (E.Z.S.), Wake Forest University School of Medicine, Winston Salem, NC; Division of Nephrology and Hypertension, St John Hospital and Medical Center, Detroit, MI (S.S.); Department of Medicine, Epidemiology and Biostatistics, University of California, San Francisco (M.G.S.); and Department of General Internal Medicine, San Francisco VA Medical Center, CA (M.G.S.).

*A list of all CRIC Study Investigators is given in the Acknowledgements.The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.

114.03311/-/DC1.Correspondence to Rajat Deo, University of Pennsylvania, 3400 Spruce St, 9 Founders Cardiology, Philadelphia, PA 19146. E-mail [email protected]

Serum Aldosterone and Death, End-Stage Renal Disease, and Cardiovascular Events in Blacks and Whites

Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study

Rajat Deo, Wei Yang, Abigail M. Khan, Nisha Bansal, Xiaoming Zhang, Mary B. Leonard, Martin G. Keane, Elsayed Z. Soliman, Susan Steigerwalt, Raymond R. Townsend,

Michael G. Shlipak, Harold I. Feldman; and the CRIC Study Investigators

© 2014 American Heart Association, Inc.

Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.114.03311

Kidney

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104 Hypertension July 2014

kidney disease6,7; however, these drugs have not been proven to reduce cardiovascular morbidity and mortality in patients with CKD.8 These medications partially suppress RAAS activation and can result in aldosterone escape9 or the ongoing induction of aldosterone production. As a result, experimental studies are seeking to understand whether more complete suppression of the RAAS with aldosterone blockers or MRBs can improve cardiorenal outcomes. This recognition has also motivated evaluation of serum aldosterone as a risk marker and potential therapeutic target especially in patients with CKD.

Activation of the RAAS has been hypothesized to explain some of the racial disparities observed in the incidence of hypertension, left ventricular hypertrophy, end-stage renal disease (ESRD), and CHF. In particular, the higher rate of hypertension-related complications seen in blacks includ-ing CKD, CHF, and death may be attributed to greater activity of downstream mediators of the RAAS including angiotensin II and aldosterone.10 The International Society on Hypertension in blacks consensus statement suggests that blacks may be particularly susceptible to the effects of RAAS activity and may have an improved response to RAAS blockade compared with whites.11 Limited studies, however, have evaluated systematically whether aldosterone is a risk factor for death and cardiorenal complications in a racially diverse cohort of CKD participants. We hypothesized that elevated aldosterone concentrations would be an indepen-dent risk factor for death, ESRD, incident heart failure, and atherosclerotic events among CKD participants. In addition, we hypothesized that this association would be stronger in blacks compared with whites.

MethodsStudy PopulationThe Chronic Renal Insufficiency Cohort (CRIC) study is a large, multicenter, multiracial, cohort study established to understand the progression of cardiovascular and renal disease among individu-als with CKD. The study enrolled subjects between June 2003 and September 2008 and was designed to include a racially and ethnically diverse group of adults. Participants who were between 21 and 74 years and had an estimated glomerular filtration rate (eGFR) between 20 and 70 mL/min per 1.73 m2 were eligible for the study. The age and eGFR criteria were specifically designed to facilitate evaluation of the progression and implications of CKD across a wide spectrum of mild-to-moderate kidney dysfunction and age. Approximately 20% of participants had an eGFR between 60 and 70 mL/min per 1.73 m2, 60% had an eGFR between 30 and 60 mL/min per 1.73 m2, and 20% had an eGFR <30 mL/min per 1.73 m2. Specific details on recruitment and design have been published previously.12 The study complies with the Declaration of Helsinki. The institutional review boards at all participating centers approved the study protocol, and study participants provided written informed consent.

In brief, CRIC recruited 3939 men and women aged 21 to 74 years. The participants underwent extensive clinical evaluations at study en-try during annual research clinic visits and via telephone interviews midway between clinic visits. Of the 3939 participants enrolled at baseline, we excluded individuals with insufficient blood specimens for aldosterone measurements (n=73), resulting in a final study sample of 3866 participants. Information on baseline confounders was obtained during the initial visit and included sociodemograph-ics, lifestyle risk factors, medical history, and medication use. Blood pressure,13 anthropometrics, ankle-brachial index,14 and other clini-cal variables were collected using standard protocols. Blood was obtained from participants in the fasting state. Measurements were made of creatinine, cystatin C, sodium, potassium, total cholesterol,

low-density lipoprotein, triglycerides, albumin, hemoglobin, se-rum calcium, phosphate, N-terminal pro–B-type natriuretic peptide (NT-proBNP), and fibroblast growth factor 23 (FGF-23). Twenty-four–hour urine samples were obtained, and urine sodium, potassium, albumin, and creatinine were measured.

MeasurementsMost measurements were performed at a central laboratory at the University of Pennsylvania. Aldosterone was measured using an ELISA kit (BioVendor, www.biovendor.com) from baseline EDTA specimens, which were collected in the fasting state and stored at −70°C until 2010. All measurements were made after a single thaw. Our estimates of the intra-assay and interassay coefficients of varia-tion ranged from 6.5% to 8.7%. NT-proBNP was measured using a chemilluminescent microparticle immunoassay (www.roche-diag-nostics.us) on the ElecSys 2010. The values ranged from 5 to 35 000 pg/mL, and the coefficient of variation was 9.3% at a level of 126 pg/mL and 5.5% at 4319 pg/mL. FGF-23 was measured in dupli-cate using stored baseline plasma samples and a C-terminal ELISA (Immunotopics). The coefficient of variation was 7.6%.15 Finally, hemoglobin was measured directly at the laboratory of each CRIC Study clinical center. eGFR was calculated from serum creatinine and cystatin C using the CRIC-based equation.16

OutcomesThe outcomes included all-cause mortality, ESRD, incident CHF, and incident atherosclerotic events. Deaths were ascertained from next of kin, retrieval of death certificates or obituaries, review of hospital records, and linkage with the social security death master file. Study participants were queried for the development of ESRD and cardiovascular events at annual follow-up visits and via semian-nual telephone interviews. ESRD was defined as initiation of dialy-sis or kidney transplantation. The cardiovascular outcomes included first hospitalization for heart failure or first atherosclerotic event, including hospitalization for myocardial infarction, cerebrovascular accident, or peripheral vascular disease. An adjudication commit-tee reviewed all relevant medical records and interviews to ascer-tain these outcomes based on well-defined criteria that have been described previously.12 All outcomes occurred between enrollment and March 31, 2011.

Statistical MethodsWe first described the baseline characteristics of CRIC partici-pants across aldosterone quartiles. Continuous variables were ana-lyzed by ANOVA and nonparametric methods for skewed variables. Categorical variables were analyzed by the χ2 test.

Separate multivariable-adjusted Cox proportional hazards mod-els were used to assess associations between aldosterone and each outcome: death, ESRD, CHF, and the atherosclerotic end point. For the analysis evaluating the risk of incident CHF and atherosclerotic events, participants with baseline cardiovascular disease and heart failure were excluded. Death was considered as a censoring event when it was not the outcome. Quadratic splines were used to explore potential nonlinearity between the log-transformed aldosterone and the outcomes of interest.17 Aldosterone was modeled as a continuous variable, and hazard ratios (HRs) were calculated per SD increment of the log-transformed variable. Aldosterone was also categorized into quartiles with the lowest quartile defined as the reference group.

Multivariable analysis was performed for each outcome adjust-ing for covariates that were potentially confounders or mediators of the association between aldosterone concentrations and cardio-renal outcomes. Adjusted models included the following covariates: demographics (age, sex, and race), clinical center, and cardiorenal risk factors including blood pressure, diabetes mellitus, eGFR, and proteinuria (24-hour urine specimen). We also adjusted for preva-lent cardiovascular disease (history of coronary artery disease, heart failure, peripheral vascular disease, and stroke) for the death and ESRD outcomes. Additional adjustment for urinary sodium, urinary sodium-to-potassium ratio, serum potassium, serum albumin, hemo-globin, and NT-proBNP was also performed. Medications known to

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Deo et al Aldosterone and Death, ESRD, and Cardiovascular Events 105

affect RAAS regulation including ACE inhibitors, ARBs, MRBs, loop diuretics, and statins were added to the multivariable model. FGF-23 was included in the ESRD analysis. The proportional haz-ards assumption was met based on cumulative Martingale residuals. We tested for interactions between aldosterone and sex, race, level of eGFR (<45 and ≥45 mL/min per 1.73 m2), use of medications that affect RAAS regulation (ACE inhibitors, ARBs, and MRBs), and use of loop diuretics for each of the outcomes assessed in this analy-sis. We also performed a prespecified, stratified analysis by race for each of the outcomes. Analyses were performed using SAS 9.2 (SAS Institute Inc, Cary, NC). All statistical tests were 2 sided, and P<0.05 were considered significant.

ResultsAmong the 3866 participants, the mean age was 58±11 years, 45% were women, and 42% were black. Approximately one third of CRIC participants had a history of cardiovascular disease at the baseline visit. The median aldosterone concen-tration was 102.1 (25th–75th percentile, 71.6–152.9) pg/mL (Figure). The mean eGFR was 45±17 mL/min per 1.73 m2, and median level of proteinuria was 0.186 (25th–75th percen-tile, 0.073–0.92) g per 24 hours.

Compared with participants in the lowest aldosterone quar-tile, those with higher levels were more likely to be men, white, had a lower eGFR, greater proteinuria, a lower urinary sodium, higher urinary potassium, less likely to be taking an ACE inhibitor, ARB, or statin, more likely to be taking a MRB or loop diuretic, and had higher levels of NT-proBNP, FGF-23, and phosphate (Table 1). In the subgroup that was not taking an ACE inhibitor, ARB, or MRB, aldosterone concen-trations were associated with most of the same baseline char-acteristics (Table S1 in the online-only Data Supplement); in addition, they correlated with hypertension, lower LDL, and higher heart rate. There was no association between serum aldosterone level and coronary artery disease, heart failure, or diabetes mellitus.

During a median follow-up of 5.4±1.6 years, there were 587 deaths, 743 ESRD events, 187 incident CHF cases, and 177 incident atherosclerotic events. The annual rates of death and ESRD were 2.8% and 3.9% in the entire study cohort, respec-tively. We used splines to estimate the risk of each adverse event across aldosterone concentrations (log-transformed).

Although the test of linearity for each of the spline functions was significant, we evaluated aldosterone both as a continuous and categorical variable.

Serum aldosterone concentrations were not associated with death or the composite atherosclerotic end point in either the unadjusted or adjusted analysis (Table 2). Among the 2571 CRIC participants without a history of cardiovascular disease at baseline, serum aldosterone concentrations were associated with the development of heart failure in unadjusted analysis. Further adjustment for demographics (age, sex, and race), clin-ical center, cardiorenal risk factors (diabetes mellitus, blood pressure, eGFR, and proteinuria), urinary and serum factors (urinary sodium, urinary sodium-to-potassium ratio, hemo-globin, serum albumin, serum potassium, and NT-proBNP), and medications (ACE inhibitors, ARBs, MRBs, loop diuret-ics, and statins) resulted in a 21% higher risk of heart failure per SD increase in log aldosterone (Table 2). Furthermore, in categorical analysis, the highest aldosterone quartile was asso-ciated with a 50% greater risk of heart failure compared with the lowest quartile; however, this association was attenuated to a 36% higher risk in multivariable analysis and nonsignifi-cant. The risk of ESRD was also higher as aldosterone concen-trations increased in unadjusted analysis. We detected a 14% higher risk per SD increase in the log-transformed aldosterone levels and a 60% higher risk in the highest aldosterone quar-tile. These estimates for ESRD risk were attenuated substan-tially after multivariable adjustment for potential confounders including FGF-23 and did not maintain statistical significance.

Interaction Testing and Subgroup AnalysisIn the evaluation of incident heart failure, we did not detect an interaction between aldosterone and race (P interaction >0.10). Subgroup analysis, however, demonstrated that the association between aldosterone and heart failure was mod-estly stronger in blacks compared with whites. For every SD increase in log-transformed aldosterone levels, the adjusted HR for CHF was 1.35 (95% confidence interval [CI], 1.08–1.69) in blacks and 1.19 (95% CI, 0.93–1.53) in whites. In addition, aldosterone was a stronger risk factor for incident heart failure in men compared with women (HR in men, 1.43; 95% CI, 1.16–1.76; HR in women, 0.98; 95% CI, 0.78–1.22; P interaction, 0.015).

For the evaluation of ESRD, we did not detect an interaction between aldosterone and race (P interaction >0.10). Subgroup analyses, however, also demonstrated that an association between aldosterone and ESRD was present in blacks and not whites. The HR for ESRD was 1.18 (95% CI, 1.04–1.35) per SD increase in aldosterone in blacks and 1.03 (95% CI, 0.88–1.21) in whites. All other interaction tests, which have not already been described above, between aldosterone and race, sex, eGFR, or use of RAAS medications or loop diuretics for the prediction of each of the 4 outcomes (death, ESRD, incident CHF, and incident atherosclerotic events) were not significant.

DiscussionAmong participants enrolled in the CRIC Study, serum aldo-sterone concentrations were marginally associated with inci-dent heart failure; however, they were not an independent risk factor for all-cause mortality, ESRD, or atherosclerotic events.

Figure. Distribution of aldosterone among Chronic Renal Insufficiency Cohort (CRIC) participants.




Table 1. Baseline Characteristics Among 3866 Participants

Baseline Variable

Aldosterone Quartiles

P Value1 (<72 pg/mL) 2 (72–102 pg/mL) 3 (103–153 pg/mL) 4 (≥153 pg/mL)

Demographics

Age, y, ±SD 59±11 58±11 58±11 58±12 0.072

Female, n (%) 495 (51) 448 (46) 373 (39) 410 (42) <0.001

Race, n (%) 0.006

Hispanic 134 (14) 136 (14) 121 (13) 103 (11)

White 396 (41) 369 (38) 405 (42) 441 (46)

Black 403 (42) 423 (44) 411 (42) 370 (38)

Prevalent cardiovascular disease, n (%)

CAD 231 (24) 207 (21) 219 (23) 195 (20) 0.23

Heart failure 78 (8) 89 (9) 105 (11) 105 (11) 0.10

PVD 58 (6) 75 (8) 70 (7) 55 (6) 0.21

Stroke 87 (9) 94 (10) 95 (10) 107 (11) 0.49

Cardiovascular risk factors

Hypertension, n (%) 822 (85) 837 (87) 834 (86) 839 (87) 0.64

Diabetes mellitus, n (%) 479 (50) 483 (50) 470 (49) 442 (46) 0.24

BMI, kg/m2, ±SD 32.1±7.7 32.4±7.9 32.2±7.7 31.8±7.9 0.37

Smoking status, n (%)

Current 128 (13) 128 (13) 128 (13) 120 (12) 0.68

Past 412 (43) 411 (43) 410 (42) 383 (40)

Never 427 (44) 427 (44) 429 (44) 463 (48)

Total cholesterol, mg/dL, ±SD 185±46 184±46 184±48 181±42 0.15

LDL, mg/dL, ±SD 104±35 102±36 102±36 101±33 0.19

Triglycerides, mg/dL, ±SD 154±111 156±113 163±120 155±118 0.35

SBP, mm Hg, ±SD 129±23 129±22 129±22 127±23 0.32

DBP, mm Hg, ±SD 71±12 71±12 72±14 72±13 0.10

Pulse, bpm, ±SD 68±11 68±11 68±12 68±12 0.94

Kidney and electrolyte parameters

Serum

eGFR, mL/min per 1.73 m2, ±SD 49.6±16.9 45.4±16.4 42.9±16.5 41.6±16.5 <0.001

eGFR categories, mL/min per 1.73 m2

>60, n (%) 232 (24) 171 (18) 146 (15) 136 (14) <0.001

30–60, n (%) 636 (66) 614 (64) 580 (60) 557 (58)

<30, n (%) 99 (10) 181 (19) 241 (25) 273 (28)

Cystatin C, mg/L, ±SD 1.4±0.5 1.5±0.5 1.6±0.6 1.6±0.6 <0.001

Serum Na, mmol/L, ±SD 139±3 139±3 139±3 139±3 0.95

Serum K, mmol/L, ±SD 4.4±0.5 4.4±0.5 4.3±0.5 4.3±0.6 <0.001

Serum Ca, mg/dL, ±SD 9.2±0.5 9.2±0.5 9.2±0.5 9.2±0.6 0.30

Serum PO4, mg/dL, ±SD 3.7±0.6 3.7±0.7 3.8±0.7 3.8±0.7 0.001

Urine

Proteinuria, g/24 h 0.14 (0.07–0.75) 0.18 (0.07–0.99) 0.23 (0.08–1.05) 0.20 (0.07–0.86) 0.007

Na excretion, mmol/24 h, ±SD 164±77 166±80 164±77 154±75 0.001

K excretion, mmol/24 h, ±SD 52±24 54±24 56±26 59±31 <0.001

Na-to-K ratio 3.5±1.8 3.4±1.6 3.2±1.5 3.0±1.6 <0.001

Biological markers

NT-proBNP, pg/mL (IQR) 137 (59–376) 147 (58–417) 160 (65–423) 166 (73–443) 0.028

FGF-23, RU/mL (IQR) 137 (94–220) 150 (98–241) 146 (98–254) 151 (94–244) 0.07

Albumin, g/dL, ±SD 3.9±0.5 3.9±0.5 4.0±0.5 4.0±0.5 <0.001

Hemoglobin, g/dL, ±SD 12.5±1.8 12.6±1.7 12.7±1.8 12.7±1.8 0.011

(Continued)




In exploratory analysis, aldosterone was a stronger risk factor for CHF in men compared with women. Although the race interactions were not significant, aldosterone concentrations seemed to be a stronger risk factor for heart failure and ESRD in blacks compared with whites. To our knowledge, this study is one of the first to evaluate systematically associations of aldosterone with cardiorenal events in a well-characterized population of CKD participants.

Our data are in contrast to prior studies that have reported an association between aldosterone and mortality and cardiovas-cular events in patients with advanced heart failure,18,19 acute myocardial infarction,20 and coronary artery disease.21–23 The lack of a strong association between aldosterone and death and cardiorenal events in our study may stem from underly-ing RAAS dysregulation that is already present in the setting of CKD. Animal models of kidney disease have demonstrated

Medications, n (%)

ACE inhibitor/ARB 682 (71) 702 (73) 662 (69) 597 (62) <0.001

Aldosterone antagonist 9 (1) 25 (3) 40 (4) 84 (9) <0.001

Loop diuretics 298 (31) 347 (36) 408 (43) 403 (42) <0.001

β-Blockers 450 (47) 473 (49) 492 (51) 483 (50) 0.31

Statins 543 (57) 563 (58) 520 (54) 495 (52) 0.012

ACE indicates angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; BMI, body mass index; CAD, coronary artery disease; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; FGF, fibroblast growth factor; IQR, interquartile range; LDL, low-density lipoprotein; NT-proBNP, N-terminal pro–B-type natriuretic peptide; PVD, peripheral vascular disease; RU, reference unit; and SBP, systolic blood pressure.

Table 1. Continued

Baseline Variable

Aldosterone Quartiles

P Value1 (<72 pg/mL) 2 (72–102 pg/mL) 3 (103–153 pg/mL) 4 (≥153 pg/mL)

Table 2. Association of Aldosterone With Death, ESRD, and Cardiovascular Outcomes in the CRIC Study

Outcome Variable

Aldosterone Quartiles Linear Model

1 2 3 4 Per SD P Value

Death

Annual event rate (No. of events/No. at risk)

2.7% (142/967) 2.6% (133/966) 3.1% (156/967) 3.0% (156/966)

Unadjusted, HR (95% CI) 1.00 (ref) 0.95 (0.75–1.21) 1.14 (0.91–1.44) 1.09 (0.87–1.37) 1.03 0.48

Adjusted,* HR (95% CI) 1.00 (ref) 0.80 (0.62–1.03) 0.92 (0.72–1.18) 0.89 (0.69–1.15) 1.00 0.98

ESRD


3.0% (145/967) 3.5% (167/966) 4.6% (214/967) 4.6% (217/966)

Unadjusted, HR (95% CI) 1.00 (ref) 1.19 (0.95–1.48) 1.58 (1.28–1.95) 1.58 (1.28–1.95) 1.14 <0.001

Adjusted,* HR (95% CI) 1.00 (ref) 0.96 (0.75–1.22) 1.08 (0.85–1.38) 1.16 (0.91–1.48) 1.06 0.15

+FGF-23, HR (95% CI) 1.00 (ref) 0.94 (0.74–1.20) 1.08 (0.85–1.37) 1.17 (0.92–1.48) 1.07 0.11

CHF


1.2% (40/643) 1.2% (39/643) 1.5% (50/643) 1.8% (58/642)


Adjusted,† HR (95% CI) 1.00 (ref) 0.82 (0.51–1.32) 1.03 (0.64–1.65) 1.36 (0.87–2.13) 1.21 0.012

Combined atherosclerotic end point


1.2% (39/643) 1.2% (40/643) 1.5% (47/643) 1.6% (51/642)


Adjusted,† HR (95% CI) 1.00 (ref) 0.94 (0.59–1.50) 0.95 (0.59–1.52) 1.28 (0.81–2.02) 1.04 0.62

CHF indicates congestive heart failure; CI, confidence interval; CRIC, Chronic Renal Insufficiency Cohort; ESRD, end-stage renal disease; FGF, fibroblast growth factor; and HR, hazard ratio.

*Adjusted for age, sex, race, clinical center, diabetes mellitus, systolic blood pressure, history of cardiovascular disease, estimated glomerular filtration rate (eGFR), urinary protein (24-h sample), urinary sodium excretion (24-h sample), urinary sodium-to-potassium ratio (24-h sample), hemoglobin, serum albumin, serum potassium, angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB) use, mineralocorticoid receptor blocker use, loop diuretic use, statin, and log N-terminal pro–B-type natriuretic peptide (NT-proBNP).

†Adjusted for age, sex, race, clinical center, diabetes mellitus, systolic blood pressure, eGFR, urinary protein (24-h sample), urinary sodium excretion (24-h sample), urinary sodium-to-potassium ratio (24-h sample), hemoglobin, serum albumin, serum potassium, ACE inhibitor/ARB use, mineralocorticoid receptor blocker use, loop diuretic use, statin, and log NT-proBNP.




upregulation of adrenal CYP11β2 (aldosterone synthase) mRNA expression.24 These models have elevated aldoste-rone concentrations and adrenal hypertrophy that precede the development of hypertension, proteinuria, and glomeruloscle-rosis.25 Although cross-sectional, we detected a reduction in eGFR and increase in proteinuria across aldosterone quartiles. Because all participants in CRIC have CKD, it is possible that merely universal dysregulation in RAAS limits the use of serum aldosterone to prognosticate mortality risk in individu-als with CKD.

Aldosterone levels are an independent risk factor for inci-dent heart failure. RAAS activation and elevations in aldo-sterone concentrations induce inflammatory and oxidative stresses that result in cardiac fibrosis.26,27 These effects are known to occur despite high or low renin levels.28 In addi-tion, although the RAAS is regulated by cardiac function and intravascular volume, our findings suggest that the aldo-sterone–incident heart failure link is independent of cardiac strain, kidney function, and total body water. We adjusted for NT-proBNP that represents neurohormonal activation and is secreted from cardiac myocytes in response to increased myo-cardial pressures and volume.29 In addition, we assessed vol-ume status by adjusting for loop diuretic use, 24-hour sodium excretion, and the 24-hour sodium-to-potassium ratio. Sodium excretion partially reflects total body sodium and water con-tent, although recent work suggests that rhythmic changes in the neuroendocrine axis regulate aldosterone concentrations and subsequently sodium content.30 Further work should assess whether aldosterone profiling can identify patients with CKD who are at the highest risk of developing CHF.

Most of the previous large-scale studies that have evaluated the association between aldosterone and mortality and cardio-vascular risk have enrolled predominantly white participants with relatively preserved kidney function.18–22 Our analysis included 1606 black participants in whom stratified analysis demonstrated a slightly higher risk of incident heart failure and ESRD. Although the interaction testing was not signifi-cant, previous small-scale studies have demonstrated the sig-nificance of aldosterone in individuals of African ancestry with hypertension.31 Specifically, plasma aldosterone levels have correlated with blood pressure and left ventricular mass in blacks but not in whites.32 More extensive work is necessary to determine whether RAAS activation comprises one of the primary pathways implicated in the disproportionately higher rates of ESRD, CHF, hypertension, and left ventricular hyper-trophy observed in blacks.

Implications for Future Clinical TrialsOur study was an observational cohort designed to provide novel insights into the relationship of the RAAS and clinical outcomes in individuals with CKD. Although aldosterone has limited ability in prognosticating risk among CKD individu-als, clinical trials to evaluate the use of MRBs in the CKD population are strongly needed. Activation of the mineralo-corticoid receptor may still occur through circulating cortisol and subsequently contribute to cardiovascular injury in indi-viduals with CKD.33,34 In CKD, the enzyme 11 β hydroxyster-oid dehydrogenase type 2, which usually inactivates cortisol to its metabolite, has reduced activity and results in cortisol

concentrations that are 100- to 1000-fold higher than aldo-sterone concentrations.35 As a result, the mineralocorticoid receptor is activated and can result in cardiovascular injury through multiple mechanisms described previously. MRBs block the actions of both cortisol and aldosterone and might explain why they remain effective in heart failure populations with normal aldosterone levels.36,37 Furthermore, a random-ized controlled trial conducted in the early stages of CKD demonstrated that adding spironolactone to an ACE inhibitor or ARB reduced left ventricular mass and arterial stiffness.38 More recently, the efficacy and safety of spironolactone were evaluated in an open-label, randomized trial among patients with ESRD on hemodialysis in the Dialysis Outcomes Heart Failure Aldactone Study. Although this trial enrolled a limited number of participants and was not blinded, it demonstrated a reduction in death or hospitalization from cardiovascular events.39 Future, prospective studies should evaluate the use of MRBs in patients with a greater range of CKD and not just those individuals on dialysis.

Several limitations of this study deserve mention. We did not measure serum renin and, therefore, could not use the aldosterone-to-renin ratio to differentiate cases of primary ver-sus secondary aldosteronism. However, we have highlighted prior work that suggests a direct link between kidney disease and increases in aldosterone production. In addition, we did not measure cortisol in the CRIC study and have specified how mineralocorticoid receptor activation and a subsequent rise in cardiovascular risk may still occur, despite the current findings. Furthermore, aldosterone was only measured at one visit and a single time point in this study, making it impossible to assess immediate and long-term changes. Variations in aldosterone concentrations occur throughout the day based on salt intake, body positioning, and other physiological parameters. The use of a 24-hour urine collection for aldosterone determination at serial intervals throughout the study follow-up period would be the most reliable means of assessing aldosterone levels in CRIC. Finally, we did not collect the duration of ACE inhibi-tor/ARB therapy among the majority of participants who were on such therapies at the baseline visit. As a result, we could not compare the significance of elevated aldosterone concentra-tions between participants who had been on RAAS inhibitors and subsequently developed the aldosterone escape phenom-ena to those that had never been on an ACE inhibitor/ARB.

The strengths of our study include the use of a large, well-characterized, multiracial cohort with rigorous adjudica-tion of cardiorenal end points and detailed characterization of markers of renal physiology and function. Aldosterone was measured at a single laboratory using a well-validated assay.

PerspectivesThe current analyses suggest that higher aldosterone concentra-tions had a modest, independent association with incident heart failure in black and white participants with CKD. Aldosterone, however, was not an independent risk factor for death, ESRD, or atherosclerotic events. This assessment is one of the first systematic evaluations of aldosterone as a potential risk factor for cardiorenal events in the CKD population. Further research is necessary to understand whether inhibition of RAAS activ-ity can prevent heart failure and other cardiorenal events in the




CKD population and whether RAAS activity can be implicated in explaining the disproportionately higher risk of cardiorenal events in blacks compared with whites.

AcknowledgmentsThe Chronic Renal Insufficiency Cohort (CRIC) Study investigators include Lawrence J. Appel, MD, MPH, Alan S. Go, MD, Jiang He, MD, PhD, John W. Kusek, PhD, James P. Lash, MD, Akinlolu Ojo, MD, PhD, and Mahboob Rahman, MD.

Sources of FundingThis work was supported by National Institutes of Health (NIH) grant K23DK089118 to R. Deo. Funding for the Chronic Renal Insufficiency Cohort (CRIC) Study was obtained under a coopera-tive agreement from National Institute of Diabetes and Digestive and Kidney Diseases (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01DK060902). In addition, this work was supported, in part, by the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award NIH/National Center for Advancing Translational Sciences (NCATS) UL1TR000003, Johns Hopkins University UL1 TR-000424, University of Maryland General Clinical Research Center M01 RR-16500, Clinical and Translational Science Collaborative of Cleveland, UL1TR000439 from the NCATS component of the National Institutes of Health and NIH roadmap for Medical Research, Michigan Institute for Clinical and Health Research UL1TR000433, University of Illinois at Chicago Clinical and Translational Science Award UL1RR029879, Tulane University Translational Research in Hypertension and Renal Biology P30GM103337, and Kaiser Permanente NIH/National Center for Research Resources UCSF-CTSI UL1 RR-024131.

DisclosuresNone.

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What Is New?

•This project from the Chronic Renal Insufficiency Cohort study is one of the first to systematically evaluate the association between serum al-dosterone levels and adverse events in blacks and whites with chronic kidney disease.

What Is Relevant?

•Activation of the renin–angiotensin–aldosterone system and subsequent increases in aldosterone levels are implicated in hypertension and chronic kidney disease.

•Elevations in aldosterone may explain the higher risk of cardiorenal events observed in individuals with chronic kidney disease.

•Aldosterone concentrations may also explain the disproportionately high-er risk of cardiorenal events in blacks compared with whites.

SummaryAmong individuals with chronic kidney disease, higher aldosterone concentrations were independently associated with the develop-ment of congestive heart failure but not for death, end-stage renal disease, or atherosclerotic events.

Novelty and Significance



and the CRIC Study InvestigatorsShlipak and Harold I. Feldman

Martin G. Keane, Elsayed Z. Soliman, Susan Steigerwalt, Raymond R. Townsend, Michael G. Rajat Deo, Wei Yang, Abigail M. Khan, Nisha Bansal, Xiaoming Zhang, Mary B. Leonard,

Blacks and Whites: Findings From the Chronic Renal Insufficiency Cohort (CRIC) StudySerum Aldosterone and Death, End-Stage Renal Disease, and Cardiovascular Events in

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SERUM ALDOSTERONE AND DEATH, END STAGE RENAL DISEASE AND

CARDIOVASCULAR EVENTS IN BLACKS AND WHITES: FINDINGS FROM

THE CRIC STUDY

SUPPLEMENTARY TABLE

Short Title: Aldosterone and Death, ESRD and Cardiovascular Events

Rajat Deo, Wei Yang, Abigail M. Khan, Nisha Bansal, Xiaoming Zhang, Mary B.

Leonard, Martin G. Keane, Elsayed Z. Soliman, Susan Steigerwalt, Raymond R.

Townsend, Michael G. Shlipak, Harold I. Feldman, and the CRIC Study Investigators

From the Division of Cardiovascular Medicine, Department of Medicine, University of

Pennsylvania, Philadelphia, Pennsylvania (R.D., A.M.K.); Center for Clinical

Epidemiology and Biostatistics and the Department of Biostatistics and Epidemiology,

University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania (W.Y., X.Z.,

M.B.L., H.I.F); Division of Nephrology, Department of Medicine, University of

Washington, Seattle, Washington (N.B.); Division of Nephrology, The Children’s

Hospital of Philadelphia, Philadelphia, Pennsylvania (M.B.L.); Division of

Cardiovascular Medicine, Temple University, Philadelphia, Pennsylvania (M.G.K.);

Epidemiological Cardiology Research Center (EPICARE), Department of Epidemiology

and Prevention, and Department of Internal Medicine, Cardiology Section, Wake Forest

University School of Medicine, Winston Salem, North Carolina (E.Z.S.); Division of

Nephrology and Hypertension, St John Hospital and Medical Center, Detroit, Michigan

(S.S.); The Renal Electrolyte and Hypertension Division, Department of Medicine,

University of Pennsylvania, Philadelphia, Pennsylvania (R.R.T.); Department of

Medicine, Epidemiology and Biostatistics, University of California, San Francisco,

California (M.G.S.); and Department of General Internal Medicine, San Francisco VA

Medical Center, San Francisco, California (M.G.S.).

Table S1. Baseline characteristics among the 1,182 participants not taking an ACE inhibitor, ARB, or MRB

Aldosterone Quartiles p-value

Baseline Variable 1

(<72 pg/ml) 2

(72-102 pg/ml) 3

(103-153 pg/ml) 4

(≥153 pg/ml)

Demographics Age ± SD

57±11

58±11

57±12

57±12

0.63

Female, n (%) 179 (63%) 139 (53%) 132 (44%) 164 (49%) <0.001 Race, n (%) White

Black Hispanic

124 (44%) 108 (38%) 40 (14%) 12 (14%)

99 (38%)

105 (40%) 44 (17%) 13 (5%)

131 (44%) 120 (40%) 37 (12%) 12 (4%)

167 (50%) 122 (36%) 39 (12%)

9 (3%)

0.27

Prevalent Cardiovascular Disease

CAD, n(%) 42 (15%) 32 (12%) 50 (17%) 54 (16%) 0.48

Heart failure, n (%) 17 (6%) 10 (4%) 20 (7%) 19 (6) 0.52

PVD, n (%) 6 (2%) 22 (8%) 25 (8%) 15 (5%) 0.002

Stroke, n (%)

17 (6%) 25 (10%) 19 (6%) 27 (8%) 0.35

CVD Risk Factors Hypertension, n(%)

176 (62%)

178 (68%)

211 (70%)

260 (77%)

<0.001

Diabetes, n(%) 86 (30%) 74 (28%) 103 (34%) 112 (33%) 0.40

BMI (kg/m2) ± SD 30.6±7.5 29.7 ± 6.4 31.1 ± 7.9 30.6 ± 8.0 0.15

Smoking Status, n(%)

Current 41 (14%) 42 (16%) 53 (18%) 57 (17%) 0.12

Past 94 (33%) 106 (41%) 128 (43%) 130 (39%)

Never 149 (53%) 113 (43%) 119 (40%) 150 (45%)

Total chol. (mg/dL) ± SD

194±43

193±46

191±52

185±43

0.087

LDL (mg/dL) ± SD 112±36 111±39 109±39 103±35 0.014 Triglycerides (mg/dL)± SD 145±99 141±79 158±111 148±107 0.23

SBP (mmHg) ± SD 128±22 128±22 130±23 127±21 0.48

DBP (mmHg) ± SD 73±11 74±12 74±13 72±12 0.58

Pulse (beats/min) ± SD 67±10 67±11 67±11 69±12 0.0295

Kidney and Electrolyte Parameters Serum eGFR (mL/min/1.73m2)± SD

55.3±20.1

50.9±19.9

45.6±19.1

43.0±19.6

<0.0001

eGFR categories (mL/min/1.73m2)

>60, n(%) 111 (39%) 83 (32%) 69 (23%) 64 (19%) <0.0001

30-60, n(%) 146 (51%) 134 (51%) 158 (53%) 167 (50%)

<30, n(%) 27 (10%) 44 (17%) 73 (24%) 106 (32%)

Cystatin C (mg/L) ± SD 1.3±0.5 1.4±0.5 1.5±0.6 1.7±0.7 <0.0001

Serum Na (mmol/L) ± SD

139±3

139±3

139±3

139±3

0.62

Serum K (mmol/L) ± SD 4.3±0.5 4.2±0.5 4.3±0.5 4.2±0.5 0.20

Serum Ca (mg/dL) ± SD 9.1±0.5 9.2±0.5 9.1±0.5 9.2±0.6 0.72

Serum PO4 (mg/dL) ± SD 3.6±0.6 3.7±0.7 3.7±0.7 3.7±0.7 0.43

Proteinuria (g/24h) 0.09 [0.06-0.35] 0.11 [0.06-0.81] 0.18 [0.07-1.06] 0.18 [0.07-0.72] 0.003

Urine

Na excretion (mmol/24 h) ± SD 149±70 158±79 155±79 143±76 0.10

K excretion (mmol/24 h) ± SD 50±24 53±25 55±28 58±35 0.010

Na to K ratio 3.5±1.9 3.4±1.8 3.1±1.4 2.8±1.7 <0.0001

Biological Markers

NT-pro BNP (pg/ml) [IQR] 124 [54-344] 129 [49-362] 157 [57-444] 185 [81-496] 0.004

FGF-23 (RU/mL) [IQR] 115 [76-192] 123 [82-208] 139 [91-257] 150 [90-270] 0.002

Albumin (g/dL) ± SD 3.9±0.5 3.9±0.5 4.0±0.5 4.0±0.5 0.33

Hemoglobin (g/dL) ± SD 12.6±1.8 12.9±1.6 12.9±2.0 12.8±1.9 0.25

Medications

Loop diuretics, n(%) 62 (23%) 73 (28%) 106 (36%) 116 (35%) 0.002

Beta blockers, n(%) 110 (40%) 110 (43%) 127 (43%) 156 (47%) 0.41

Statins, n(%) 100 (37%) 120 (47%) 118 (40%) 134 (41%) 0.013

ACE, angiotensin converting enzyme; ARB, angiotensin II receptor blockers; MRB mineralocorticoid receptor blocker;

CAD, coronary artery disease; PVD, peripheral vascular disease; BMI, body mass index; LDL, low density lipoprotein;

SBP, systolic blood pressure; DBP, diastolic blood pressure; NT-pro BNP, N-terminal pro-B-type natriuretic peptide; FGF,

fibroblast growth factor.

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